| Structural highlights
6bz4 is a 2 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
| | Ligands: | , , , , |
| Related: | 4wi2, 4wi3, 4wi4, 4wi5, 4wi6, 4wi7, 4wi8, 4wi9 |
| Resources: | FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT |
Function
[IGG1_HUMAN] Immunoglobulins, also known as antibodies, are membrane-bound or secreted glycoproteins produced by B lymphocytes. In the recognition phase of humoral immunity, the membrane-bound immunoglobulins serve as receptors which, upon binding of a specific antigen, trigger the clonal expansion and differentiation of B lymphocytes into immunoglobulins-secreting plasma cells. Secreted immunoglobulins mediate the effector phase of humoral immunity, which results in the elimination of bound antigens (PubMed:22158414, PubMed:20176268). The antigen binding site is formed by the variable domain of one heavy chain, together with that of its associated light chain. Thus, each immunoglobulin has two antigen binding sites with remarkable affinity for a particular antigen. The variable domains are assembled by a process called V-(D)-J rearrangement and can then be subjected to somatic hypermutations which, after exposure to antigen and selection, allow affinity maturation for a particular antigen (PubMed:20176268, PubMed:17576170).[1] [2] [3]
Publication Abstract from PubMed
Antibody engineering is important for many diagnostic and clinical applications of monoclonal antibodies. We recently reported a series of Fc mutations targeting the neonatal Fc receptor (FcRn) site on a Lewis Y binding IgG1, hu3S193. The hu3S193 variants displayed shortened in vivo half-lives and may have potential for radioimaging or radiotherapy of Lewis Y positive tumors. Here we report Fc crystal structures of wild-type hu3S193, seven FcRn binding site variants, and a variant lacking C1q binding or complement-dependent cytotoxicity (CDC) activity. The Fc conformation of the FcRn binding sites were similar for wild-type and all mutants of hu3S193 Fc, which suggests FcRn interactions were directly impacted by the amino acid substitutions. The C1q binding site mutant Fc was nearly identical to the wild-type Fc. Surprisingly, several hu3S193 Fc variants showed large changes in global structure compared to wild-type Fc. All hu3S193 Fc mutants had similar antibody-dependent cellular cytotoxicity (ADCC) despite some with conformations expected to diminish Fc gamma receptor binding. Several hu3S193 variants displayed altered CDC, but there was no correlation with the different Fc conformations. All versions of hu3S193, except the C1q binding site mutant, bound C1q suggesting that the altered CDC of some variants could result from different propensities to form IgG hexamers after engaging Lewis Y on target cells. Overall, our findings support the concept that the antibody Fc is both flexible and mobile in solution. Structure-based design approaches should take into account the conformational plasticity of the Fc when engineering antibodies with optimal effector properties.
Global conformational changes in IgG-Fc upon mutation of the FcRn binding site are not associated with altered antibody-dependent effector functions.,Burvenich IJG, Farrugia W, Liu Z, Makris D, King D, Gloria B, Perani A, Allan LC, Scott AM, Ramsland PA Biochem J. 2018 May 24. pii: BCJ20180139. doi: 10.1042/BCJ20180139. PMID:29794155[4]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Teng G, Papavasiliou FN. Immunoglobulin somatic hypermutation. Annu Rev Genet. 2007;41:107-20. PMID:17576170 doi:http://dx.doi.org/10.1146/annurev.genet.41.110306.130340
- ↑ Schroeder HW Jr, Cavacini L. Structure and function of immunoglobulins. J Allergy Clin Immunol. 2010 Feb;125(2 Suppl 2):S41-52. doi:, 10.1016/j.jaci.2009.09.046. PMID:20176268 doi:http://dx.doi.org/10.1016/j.jaci.2009.09.046
- ↑ McHeyzer-Williams M, Okitsu S, Wang N, McHeyzer-Williams L. Molecular programming of B cell memory. Nat Rev Immunol. 2011 Dec 9;12(1):24-34. doi: 10.1038/nri3128. PMID:22158414 doi:http://dx.doi.org/10.1038/nri3128
- ↑ Burvenich IJG, Farrugia W, Liu Z, Makris D, King D, Gloria B, Perani A, Allan LC, Scott AM, Ramsland PA. Global conformational changes in IgG-Fc upon mutation of the FcRn binding site are not associated with altered antibody-dependent effector functions. Biochem J. 2018 May 24. pii: BCJ20180139. doi: 10.1042/BCJ20180139. PMID:29794155 doi:http://dx.doi.org/10.1042/BCJ20180139
|
